System and method for the automated processing of fluids, method for determining the matching of objects

ABSTRACT

A system and method for the automated processing of fluids according to a process operation plan involving the use of preloaded objects, which are to be present in target object positions, are disclosed. The system includes: a processing area in which objects to be used for the processing of fluids are located; at least one ultrasonic sensor for determining the presence of objects by acoustical waves; a positioning device to which the ultrasonic sensor is fixed and which moves the ultrasonic sensor in at least one direction relative to the processing area; a control computer determining the presence of objects and determining if objects are present in target object positions in the processing area as defined by the process operation plan; a pipetting device for pipetting of fluids between cavities located in the processing area; and an analytical or pre-analytical processing device for processing of fluids located in the processing area.

TECHNICAL FIELD

Embodiments of the present invention relate generally to automatedsystems for the analytical or pre-analytical processing of fluids, andmore particularly to a system and method for the automated processing offluids according to a process operation plan involving the use ofpreloaded objects. It further relates to a method for determining thematching of objects in an instrument with preloaded objects to bepresent in target object positions according to a process operationplan.

BACKGROUND

In these days, various types of clinical analyzers for the automatedprocessing of biological fluids such as blood, serum and urine are beingin practical use. Sample preparation and analysis of biological fluidsbasically involves handling and mixing of the fluids using variouscomponents such as multi-well plates, pipette trays, pipette tips andbottles filled with reagents, buffers, wash solutions and the like,which may be subsumed by the generic term “consumables”. When operablein a stand-alone mode, analyzers typically are manually preloaded withconsumables needed for the processing of fluids prior to starting theautomated fluid processing.

Since there is a strong demand for offering a wide variety of analyticaloptions and with a view to improve effectiveness in sample processing,analyzers often process samples in parallel and/or split each sampleinto a number of sample aliquots for the simultaneous processing thereofdeploying different analytical techniques. Due to the high samplethroughput and dependent on the number of analytical options offered,modern apparatus are subject to an elevated consumption of consumableswhich they have to be charged with.

However, in daily routine, a problem may occur that consumables neededfor the automated processing of fluids are misplaced or even missingbecause of human error when manually preloading the analyzer. Albeit,even in case of automatically preloading of consumables, since there isa risk of dropping or misplacing of objects due to misalignment errors,misplacement or absence of consumables cannot be excluded. Thisespecially applies to the case of modern analyzers which, according tothe above, normally are subject to an elevated consumption ofconsumables requiring many preloading operations.

In modern analyzers, missing or misplaced consumables will automaticallycause a stop of a current run which entails a delay for starting thenext run and may also give rise to repeat the aborted run which lowersefficiency in fluid processing. Even worse, accidental stops mayconstitute a need to discard the fluid samples currently processed,which has to be avoided since some fluids require delicate extractionoperations or are unique in a sense that they cannot be reproduced suchas in forensic applications.

SUMMARY

It is against the above background that embodiments of the presentinvention provide a system and method for the automated processing offluids involving the use of preloaded consumables to enable reliablefluid sample processing without a risk of interrupting an ongoing rundue to missing or misplaced consumables.

In one preferred embodiment, a system for the automated processing offluids according to a process operation plan involving the use ofpreloaded objects, said process operation plan defining preloadedobjects to be present in target object positions, is disclosed. Thesystem comprises: a processing area in which objects to be used for theprocessing of fluids are located; at least one ultrasonic sensor fordetermining the presence of objects by acoustical waves; a positioningdevice to which the ultrasonic sensor is fixed and which moves theultrasonic sensor in at least one direction relative to said processingarea; a control computer determining the presence of objects anddetermining if objects are present in target object positions in saidprocessing area as defined by said process operation plan; at least onepipetting device for pipetting of fluids between cavities located insaid processing area; and an analytical or pre-analytical processingdevice for processing of fluids located in said processing area.

In another preferred embodiment, a method is disclosed for determiningthe matching of objects present in a processing area in an instrumentwith preloaded objects to be present in target object positions in saidinstrument according to a process operation plan. The method comprises:determining the presence of objects relative to the processing area insaid instrument by means of at least one ultrasonic sensor; anddetermining if objects are present in target object positions as definedby said process operation plan.

Other and further embodiments, features and advantages of the inventionwill appear more fully from the accompanying drawings, the followingdetailed description, and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, like designations denote like or similar elements, andin which:

FIG. 1 is an elevational partial view illustrating an exemplaryembodiment of the system of the invention, adapted for the extraction ofnucleic acids;

FIG. 2 is a top view of the system of FIG. 1;

FIG. 3 is another top view of the system of FIG. 1;

FIG. 4 is a flow chart illustrating exemplary process steps for theprocessing of nucleic acids containing fluids according to a processoperation plan;

FIGS. 5A-5B are flow charts illustrating exemplary process steps whichmay be performed during extraction of nucleic acids according to theprocess operation plan;

FIG. 6 is a diagram depicting a time-of-travel curve for determiningliquid levels in the system of FIG. 1; and

FIG. 7 is an exemplary screen display of target positions of objects.

REFERENCE LIST

-   1 System-   2 Work-plate-   3 Waste rack-   4 Processing rack-   5 Tip tray rack-   6 First reagent rack-   7 Second reagent rack-   8 Bottle rack-   9 Rib-   10 Rack opening-   11 Front side-   12 Retaining section-   13 Waste tip tray-   14 Waste liquid tray-   15 Processing plate-   16 Output plate-   17 Tip tray-   18 Reagent plate-   19 Bottle cartridge-   20 Bottle-   21 First pipettor-   22 Pipetting tip-   23 Positioning device-   24 First guiding rail-   25 Second guiding rail-   26 Second pipettor-   27 Sensor array-   28 Ultrasonic sensor-   29 Transfer head-   30 First pipette-   31 Second pipette-   32 Arrow-   33 Arrow-   34 Control computer-   35 Display-   36 Processing device-   37 Reagent

DETAILED DESCRIPTION

According to one embodiment of the invention, a system for the automatedanalytical or pre-analytical processing of fluids (fluid samples)according to a process operation plan involving the use of preloadedobjects for automatically processing the fluids is provided. The processoperation plan which may be embodied as a computer program for runningon a programmable control computer instructs operations to be performedfor automatically processing the fluids. Specifically, the processoperation plan defines objects which are required for the automatedprocessing of fluids and, thus, have to be preloaded in advance ofstarting the automated processing of fluids. The process operation planalso defines target object positions for each of the objects to bepreloaded in advance of starting the automated processing of fluids,that is to say, it defines object positions into which the objects areintended to be preloaded prior to starting the automated processing offluids.

Accordingly, a system for the automated processing of fluids isprovided, which comprises a processing area in which objects to be usedfor the processing of fluids are located. As used herein, the term“processing area” describes an area of the system, in which theautomated processing of fluids is being performed.

The system further comprises at least one ultrasonic sensor, adapted fordetermining the presence of objects in said processing area by means ofacoustic waves. Ultrasonic sensors for emitting ultrasonic waves towardsan object of measurement and receiving acoustic waves returning uponreflection at the object are well-known to those of skill in the art,and, for instance, are described in European patent specification EP0732598 B1. Accordingly, an ultrasonic sensor includes at least onetransducer used for emitting of acoustic waves in a transmitting modeand receiving of reflected acoustic waves in a receiving mode, whichmodes may be changed by a change-over switch. More specifically, intransmitting mode, drive pulses may be fed to the transducer to generateacoustic waves emitted to the object of measurement. On the other hand,in receiving mode, the transducer detects reflected acoustic waveswhich, for instance, are fed to a sampling circuit to be sampled at apredetermined frequency and to then be converted into digital data.

The system further comprises a positioning device to which the at leastone ultrasonic sensor is fixed, adapted to move the ultrasonic sensor inat least one direction relative to the processing area. For thatpurpose, the ultrasonic sensor is fixed to a positioning member (e.g. atransfer head) of the positioning device.

The system further comprises a control computer for controlling of theautomated processing of fluids according to the process operation planwhich, for instance, may be embodied as a programmable control computerrunning a computer-readable program provided with instructions toperform operations in accord with the process operation plan. Thecontrol computer may, e.g., include functional entities such asmicroprocessors dedicated to the control of specific system componentsunder main control of the control computer. The functional entities maybe integrated in these system components. In that, the control computeris electrically connected to the system components which require controlas specified by the process operation plan which include the positioningdevice and the ultrasonic sensor. The control computer receivesinformation from the different components of the system and generatesand transmits corresponding control signals for controlling thecomponents according to the process operation plan. The control computercan be connected to the system components via one or more dataconnections, e.g., by use of a wired or wireless network.

More particularly, in the system of the invention, the control computeris being configured to determine the presence of objects and todetermine if objects are present in target object positions in saidprocessing area as defined by said process operation plan. In that, thecontrol computer may generate control signals for coordinating movementsof the at least one ultrasonic sensor relative to the processing areaand, by means of the ultrasonic sensor, determining if objects to beused for the automated processing of fluids are present in the targetobject positions as defined by the process operation plan.

The control computer may, for instance, be configured in a way thatdetermination of the presence of individual objects is based ondetermining a difference of signal values (e.g. time between emission ofacoustic waves and reception of reflected acoustic waves) between firstand second signals values, with first signal values corresponding toacoustic waves reflected from surfaces located at least in the targetobject positions and with second values corresponding to acoustic wavesreflected from surfaces located in reference positions. The referencepositions preferably are provided by surfaces of the holder.

Alternatively, the control computer may, for instance, be configured ina way that determination of the presence of individual objects is basedon determining of differences of distances between first and seconddistances of surfaces reflecting the first and second acoustic waves,respectively.

The control computer may be configured to determine the presence ofobjects and determining if objects are present in target objectpositions as defined by said process operation plan performing a controlrun in advance of starting the automated processing of fluids and/orduring the automated processing of fluids.

The control computer may be configured to generate control signals todetermine an identity and/or an orientation of individual objects asdetermined by the process operation plan, for instance, in determiningan object profile (pattern), in particular a height profile, of theobject concerned and comparing the object profile as determined with anobject profile as defined by the process operation plan.

The control computer may also be configured to generate control signalsbased on a result of the determination if objects are present in targetobject positions as defined by the process operation plan which aresupplied to a signalizing device, e.g. a display, to generate auser-identifiable message, so that a user may be informed about lackingand/or misplaced objects for use in the automated fluid processing. Themessage may, for instance, contain information for guiding a user formanually or automatically loading of missing and/or misplaced objects tobe used in fluid processing as defined by the process operation plan.

Specifically, the control computer may, e.g., be configured to controlthe signalizing device in a manner to signalize a mismatch (difference)between objects actually present and objects required at target objectpositions as defined by the process operation plan.

Specifically, the control computer may, e.g., be configured to control adisplay in a manner to display a (e.g. schematic) representation of oneor more parts of the system in order to visualize the target objectpositions as defined by the process operation plan. In that, the displaycan, e.g., be controlled to display one or more parts of the processingarea. More specifically, the control computer may, e.g., be configuredto control the display in a manner to display a mismatch (difference)between objects actually present and objects required at target objectpositions as defined by the process operation plan.

Otherwise, the control computer may be configured to control the displayin a manner to display the objects at target object positions as definedby the process operation plan, followed by displaying a mismatch betweenobjects actually present and the objects required at target objectpositions as defined by the process operation plan, e.g. after detectinga manipulation of the system and/or after elapse of a pre-determinedtime span, in order to display the result of a manual and/or automaticloading operation for charging the system with the required objects.

Specifically, the process operation plan may include a section whichguides a user in loading the system with objects. Such a section foruser guidance may involve the display of a representation of theprocessing area of the system and the objects to be loaded on a display.The process operation plan may further comprise a section for signallingloading mistakes to the user to facilitate ramification of the loadingmistakes.

The system further comprises at least one pipetting device for pipettingof fluids between cavities located in the processing area.

The system yet further comprises at least one analytical orpre-analytical processing device for processing of fluids located in theprocessing area. Analytical processing devices which are being used foranalytically processing the fluids typically include a light sourceilluminating sample fluids and a detector receiving radiation emitted,transmitted or reflected from the sample such as colorimetric measuringunits, fluorescence measuring units and the like. Further, electricalmeasuring devices such as coulometric, conductometric or potentiometric(e.g. ion-selective electrodes) measuring devices can be employed.Pre-analytical processing devices which are being used forpre-analytically processing the fluids (prior to analytically processingthe fluids) typically include heating or incubation devices, magneticseparation devices, centrifugation devices, dilution and aliquotationunits. As above-detailed, functional entities of the control computercan, e.g., be integrated in the analytical or pre-analytical processingdevice for the control thereof. Otherwise, the control computer is beingconnected to the analytical or pre-analytical processing device, e.g.,by means of a network.

The system may further comprise at least one holder, adapted to hold theobjects to be used for the automated processing of fluids in the targetobject positions as defined by the process operation plan. The holdermay, for instance, be embodied as a movable rack which can be moved intoan inoperative position for loading/unloading with objects and anoperative position for use of the preloaded objects when performing theautomated processing of fluids. In that, the holder preferably holds amulti-well plate provided with cavities having defined positions. Theholder is preferably kept stationary during determining of the presenceof objects.

Hence, enabling an automated determination if objects are present intarget object positions as defined by the process operation planadvantageously allows for highly reliable automated processing of fluidswhich especially applies to the case of modern instruments requiringfrequent preloading operations which are likely to cause errors as permissing or misplaced objects.

The system for the automated processing of fluids may be configured invarious ways in accordance with the specific demands of users as long asautomated processing of fluids involves the use of preloaded objects. Inthat, the system for automatically processing of fluids may be embodiedas analyzer for analyzing of fluids typically involving mixing of thefluids with reagents to determine presence and amount or absence ofspecific substances contained in the fluids. It may also be embodied asa pre-analytic sample preparator for the automated preparation of fluidsamples prior to analysis such as an extractor for the automatedextraction of nucleic acids prior to amplification.

Fluids to be automatically processed in the system may includebiological fluids (e.g. blood, serum, urine, cerebrospinal fluids andnucleic acids (DNA/RNA) containing fluids), non-biological fluids (e.g.chemical compounds and drugs) and any other fluid of interest as long asautomated processing thereof involves the use of preloaded objects.

The term “processing of fluids” as used herein may relate to asingle-step process for automatically processing of fluids so thatobjects to be used for the automated processing of fluids are beingpreloaded in advance of starting the automated processing of fluids. Itmay also relate to a multi-step process for automatically processing offluids in which objects to be used for the automated processing offluids are being preloaded in advance of starting the first step and/orduring a time-interval in-between consecutive process steps. In thelatter case, starting of the automated processing of fluids may eitherrelate to starting the multi-step process or starting of any individualprocess step thereof.

The term “preloading” of objects as used herein refers to any manualand/or automated loading operation in advance of starting the automatedprocessing of fluids to be kept in readiness for use in the automatedprocessing of fluids. Automated loading of objects may be performedusing a manipulator such as a robotic arm. Automatically loading ofobjects requires control, since problems as to missing or misplacedobjects may occur, for instance, in case objects remain sticking on therobotic arm.

Objects to be used for the automated processing of fluids most typicallyare disposables which include plates forming cavities such as multi-wellplates, pipette trays for receiving pipette tips, pipette tips andcontainers containing various liquids such as reagents, suspensions ofmagnetically attractable particles, buffers, wash solutions and thelike.

It may be preferred that the system comprises a plurality of ultrasonicsensors which are arranged in a linear (one-dimensional) or planar(two-dimensional) array for simultaneously determining the presence ofobjects. In that case, the control computer is configured to coordinatea plurality of ultrasonic sensors in parallel to simultaneouslydetermine the presence of objects, advantageously increasing efficiencyin sample processing which results in an increased sample throughput andreliability.

In the above embodiment, it may be preferred to arrange a plurality ofultrasonic sensors in a linear array extending in a first direction inaccord with a planar array of objects extending in the first directionand a second direction with are in orthogonal relationship with respectto each other, wherein the inter-distance of ultrasonic sensorscorresponds to the inter-distance of objects in the first direction.Particularly, a number of ultrasonic sensors may correspond to aninteger divisor of a number of objects. In that case, a planar array ofobjects may be efficiently controlled to determine if objects arepresent in target object positions as defined by the process operationplan. Specifically, the control computer may be configured to controldetermining of the presence of objects based on determining a differenceof signal values between first and second signals values, with the firstsignal values corresponding to acoustic waves reflected from surfaces atleast located in the target object positions and a second signal valuecorresponding to acoustic waves reflected from a surface as given by theplane the objects are arrayed in. Using such reference plane, errors indetermining presence of objects due to varying positioning of theultrasonic sensor relative to the holder may advantageously be avoided.

According to another preferred embodiment of the system of theinvention, the system further comprises a pipetting device which isprovided with at least one pipette for pipetting of liquids for theautomated processing of fluids. In that case, the positioning devicepreferably is adapted for moving both the at least one ultrasonic sensorand the at least one pipette for pipetting of liquids. Preferably the atleast one ultrasonic sensor and the at least one pipette are both fixedto the same positioning device. The use of a single positioning devicesaves costs and space, avoids a risk of collision between differentpositioning devices and simplifies control thereof. On the other hand,configuring the control computer in a way that moving of the at leastone ultrasonic sensor for determining the presence of objects iscombined with moving of the at least one pipette for pipetting ofliquids for the automated processing of fluids, efficiency in theautomated processing of fluids may be increased.

According to another embodiment of the invention, a method is providedfor determining the matching of objects present in a processing area inan instrument with preloaded objects to be present in target objectpositions in the instrument according to a process operation plan. Themethod may comprise the following steps.

A step of determining the presence of objects relative to the processingarea in the instrument by means of at least one ultrasonic sensor. Suchstep may include moving the at least one ultrasonic sensor relative tothe processing area in the instrument.

A step of determining if objects are present in target object positionsas defined by the process operation plan.

The above method of the present invention advantageously allows for anautomated control of presence of objects in the intended target objectpositions in the processing area as defined by the process operationplan.

In case of mismatch between the presence of objects as defined by theprocess operation plan and the actual presence of objects, preferably astep of outputting a message based on the result of the determination toa signalizing device such as a display is performed. The message may,e.g., contain user-guiding information for guiding a user with respectto loading of missing and/or misplaced objects to be loaded into theinstrument.

Specifically, the signalizing device can, e.g., be controlled tosignalize a mismatch between the objects present and objects required intarget object positions as defined by the process operation plan. Morespecifically, a display can, e.g., be controlled to display arepresentation of one or more parts of the system, which e.g. can be oneor more parts of the processing area, in order to visualize the targetobject positions as defined by the process operation plan. In that, thedisplay can, e.g., be controlled to display the objects required attarget object positions as defined by the process operation plan.Otherwise, the display can also be controlled to display a mismatchbetween objects actually present and objects required in target objectpositions as defined by the process operation plan. The display can,e.g., be controlled to display the objects required at the target objectpositions as defined by the process operation plan, followed bydisplaying a mismatch between objects actually present and objectsrequired in target object positions as defined by the process operationplan, e.g. after detecting a manipulation of the system and/or afterelapse of a pre-determined time span, in order to display the result ofa manual and/or automatic loading operation for charging the system withthe required objects.

According to a preferred embodiment of the method of the invention,determining of presence of objects involves measuring of first signalvalues (e.g. time between emission of acoustic waves and reception ofreflected acoustic waves) of first acoustic waves received uponreflection at surfaces at least in the target object positions andcomparing the first signal values with at least one second signal valuereceived upon reflection at a surface in a reference position.

According to another preferred embodiment of the method of theinvention, determining of presence of objects involves measuring offirst distance values of acoustic waves received upon reflection atsurfaces at least in said target object positions and comparing saidfirst distance values with at least one second distance value receivedupon reflection at a surface in a reference distance position.

According to yet another preferred embodiment of the method of theinvention, a step of determining object identities of individual objectsand determining if there is matching between object identities asdetermined and object identities as defined by the process operationplan is performed.

According to yet another preferred embodiment of the method of theinvention, a step of determining object orientations of individualobjects and determining if there is matching between object orientationsas determined and object orientations as defined by the processoperation plan is performed.

According to yet another preferred embodiment of the method of theinvention, a step of moving a (linear or planar) array of ultrasonicsensors relative to the processing area in the instrument may beperformed. Hence, presence of objects may be determined in parallel tothereby advantageously increase efficiency in fluid processing. Inparticular, in case of a planar array of cavities containing the fluidsto be processed, in which the cavities being arranged side by side in arow extending in a first direction and plural rows are stacked one uponthe other in a second direction, with the first and second directionsbeing in orthogonal relationship with respect to each other, it may bepreferable that a linear array of ultrasonic sensors having the sensorsarrayed along the first direction is moved along the first and/or thesecond direction.

According to yet another preferred embodiment of the method of theinvention, moving of the at least one ultrasonic sensor for determiningof presence of objects in the processing area is combined with moving ofat least one pipette for pipetting of liquids for the automatedprocessing of fluids. Combining movements of the at least one ultrasonicsensor and the at least one pipette, efficiency in sample processing mayadvantageously be increased.

According to yet another preferred embodiment of the method of theinvention, it further includes a step of determining liquid levels ofliquids contained in cavities by means of the at least one ultrasonicsensor. Such embodiment advantageously allows for control of liquidlevels in order to control presence of fluids and/or outcome ofpipetting operations performed in the automated fluid processing. Inthat case, it may be preferable to determine fluid levels involvingmeasuring of distance values with respect to a reference distance levelas defined by a plane of a planar array of cavities.

According to another embodiment of the invention, a method is providedfor the automated processing of fluids according to a process operationplan involving the use of preloaded objects which includes a method fordetermining the matching of objects present in a processing area in aninstrument with preloaded objects to be present in target objectpositions in the instrument according to the process operation plan asabove-described.

The embodiments of the present invention will now be described ingreater detail below with reference to the accompanying drawings, wherelike designations denote like or similar elements.

Referring to FIGS. 1 through 7, an exemplary embodiment of the systemand method according to the invention is explained. Accordingly, asystem 1 (instrument) for the automated processing of nucleic acidscontaining fluids is described which permits extraction of nucleic acidsprior to their amplification. Alternatively, the present invention canbe employed in other systems such as in clinical analyzers and the like.

The system 1 includes a horizontal work-plate 2 which may be identifiedas processing area is provided with a plurality of rack openings 10arranged side by side with respect to each other, each of which beingadapted for accommodating elongated racks 3-8. Each rack opening 10 maybe accessed by a slot-like aperture at a front side 11 of the system 1allowing the racks 3-8 to be inserted into the rack openings 10 andremoved therefrom, respectively. For that purpose, each rack 3-8 isprovided with two lateral ribs 9 linearly extending in parallelrelationship with each other which, when inserting the racks 3-8 intothe rack openings 10, get into fitting engagement with grooves formed bythe work-plate 2 to slidably support the racks 3-8.

The system 1 comprises a number of six racks 3-8 including a waste rack3, a processing rack 4, a tip tray rack 5, a first reagent rack 6, asecond reagent rack 7 and a bottle rack 8. Individual racks are beingprovided with a number of retaining sections 12 to accommodate and holdvarious objects such as multi-well plates, tip trays and bottlecartridges, and thus define various target object positions with thesystem 1. In FIG. 2, the waste rack 3 is shown to be loaded with threewaste tip trays 13 to receive waste tips and a waste liquid tray 14 toreceive waste liquid, the processing rack 4 is shown to be loaded withtwo processing plates 15 (deep-well plates) to receive nucleic acidscontaining fluids used as starting materials for the extraction ofnucleic acids and two output plates 16 to receive solutions containingthe extracted (purified) nucleic acids, the tip tray rack 5 is providedwith four tip trays 17 filled with tips, the first and second reagentracks 6, 7 may be loaded with various processing solutions such asbuffer and wash solutions (not further detailed in the figures) and areshown to be loaded with reagent plates 18 for mixing of reagentcontaining solutions, and the bottle rack 8 is provided with severalbottle cartridges 19 for supporting of bottles 20 containing variousliquids such as enzymes and suspensions of magnetic particles.

Accordingly, the racks 3-8 are provided with plural consumables to beused for the automated extraction of nucleic acids which have to bemanually or automatically preloaded prior to starting the extraction ofnucleic acids. For that purpose, individual racks 3-8 can be partly orcompletely put out of the rack openings 10 for manual or automatedloading and/or unloading operations as above-detailed. For the purposeof illustration only, in FIG. 3, the processing rack 4 is shown to bepartly pulled out of the rack opening 10.

While FIGS. 2 and 3 depict specific numbers of system components such asracks, retaining sections, plates, trays and bottle cartridges, it is tobe understood that these numbers may vary in accord with specific needsfor the extraction of nucleic acids.

As exemplified in the present embodiment, individual plates are providedwith a planar array of 96 wells with 8 wells arranged side by side in arow extending in a first direction and 12 rows stacked one upon theother in a second direction, with the first and second directions beingin orthogonal relationship with respect to each other. Consistentlytherewith, individual tip trays include 96 tips. It, however, is to beunderstood that differently sized arrays may alternatively be used inaccordance with specific needs for the extraction of nucleic acids.

The system 1 comprises a first pipettor 21 including 96 first pipettes30 provided with disposable pipetting tips 22, adapted to transferfluids to or from the plates. More specifically, the first pipettes 30are mounted to a transfer head 29 of a positioning device 23 which canbe moved in a first direction of travel towards and away from thework-plate 2, for instance by means of a spindle drive, and in secondand third directions of travel in a plane, with the second and thirddirections being in orthogonal relationship with respect to the firstdirection, by means of first and second guiding rails 24, 25. Since suchpositioning device 23 is well-known to those of skill in the art, it isnot further detailed herein. The first pipettor 21 can thus be movedrelative to the racks 3-8 for pipetting of liquids for the automatedprocessing of fluid samples.

The system 1 further includes a second pipettor 26 including a pluralityof second pipettes 31, adapted to transfer fluids to or from the plates,which is not further detailed herein.

The system yet further includes a linear array 27 of eight ultrasonicsensors 28, adapted to determine the presence of objects by means ofacoustic waves which are secured to the transfer head 29 and thus can bemoved together with the first pipettor 21 with respect to the racks 3-8.Stated more particularly, the linearly arrayed ultrasonic sensors 28extend along the same direction (first direction) as each row ofindividual plates, wherein a distance in-between adjacent ultrasonicsensors 28 matches a distance in-between adjacent wells.

A programmable control computer 34 is used for controlling of theautomated processing of nucleic acids containing fluids for theextraction of nucleic acids according to a predetermined processoperation plan. Accordingly, the control computer 34 runs acomputer-readable program which is provided with instructions to performautomated operations in accord with the process operation plan. In that,the control computer 34 is electrically connected to the systemcomponents which require control as specified by the process operationplan which include the positioning device 23 and the ultrasonic sensors28. Data connection between the control computer 34 and the systemcomponents is by plural data connections (not illustrated) which can bepart of a network for transferring data. The control computer 34 may bean off-the-shelf computer programmed to run the process operation planfor controlling the system 1.

Aside from instructing operation steps, the process operation plandefines the consumables which are required for the automated extractionof nucleic acids and thus have to be preloaded in advance of startingthe fluid handling steps. In particular, it defines intended positions(target object positions) of consumables with respect to the racks 3-8into which the consumables are to be placed when preloaded. It alsodefines intended positions (target object positions) of consumables withrespect to individual plates, trays and cartridges into whichconsumables such as tips and bottles are to be placed when preloaded.The process operation plan may optionally also define identity and/ororientation with respect to the intended position of individualconsumables to be used for the automated extraction of nucleic acids.

The control computer 34 further includes a display 35 (signalizingdevice) for displaying graphical representations and/or messages to beread by the user. In order to enable manual data input, the controlcomputer 34 can, e.g., include a key panel (not illustrated). Otherwise,the display 35 can, e.g., be embodied as touch-screen to displayinformation and enter data.

The system 1 further includes a pre-analytical processing devicegenerally referred to at 36 for processing of fluids located on thework-area 2. The processing device 36, e.g., includes heating andmagnetic separation devices (not illustrated) for the automatedextraction of nucleic acids. Since extraction of nucleic acids iswell-known to those of skill in the art it is not further herein.

Reference is made to FIG. 4 depicting a flow chart illustratingexemplary process steps for the processing of nucleic acids containingfluids according to the process operation plan.

The symbols of the flowchart have the following meaning:

-   -   I: START    -   II: DISPLAY PROCESS OPERATION PLANS    -   III: SELECT A PROCESS OPERATION PLAN    -   IV: START SUBROUTINES “CHECK PRESENCE AND FLUID LEVEL”    -   V: MISMATCH?    -   VI: DISPLAY MESSAGE    -   VII: INITIATE RE-START SUBROUTINE “CHECK PRESENCE AND/OR FLUID        LEVEL”    -   VIII: START SUBROUTINE “EXTRACTION”    -   XI: END

Accordingly, beginning with starting the process (process step I), e.g.,when powering-up system 1, different process operation plans aredisplayed (process step II) on the display 35 for selection by a user.After manually and/or automatically preloading various consumables andthe nucleic acids containing solutions, actuating the control computer34, the user can select a process operation plan according to thespecific operations to be performed for the processing of nucleic acidscontaining fluids (process step III).

As above-detailed, the process operation plan defines the consumableswhich are to be used for the processing of nucleic acids containingfluids, as well as target positions, identities and orientations withrespect to the intended position of individual consumables. It may beprovided that the user can also enter various process parameters fortailoring the process operation plan to specific needs.

Having a process operation plan selected as desired, a subroutine “CHECKPRESENCE” (process step IV) starts. This subroutine starts a control runin which the sensor array 27 of ultrasonic sensors 28 is moved over theracks 3-8 to determine if consumables are present in their intendedpositions as defined by the process operation plan.

For the purpose of illustration only, it is now assumed that, accordingto the process operation plan, the extraction of nucleic acids needs twoprocessing plates 15 filled with nucleic acids containing solutions andfour tip trays 17 filled with pipetting tips to be placed in thecorresponding retaining sections 12 of the processing rack 4 and tiptray rack 5, respectively, which thus define target object positions.

The display 35 can, e.g., display the work-plate 2 or one or more partsthereof to visualize the consumables at their intended positionsrequired for the processing of the fluids, i.e. extraction of nucleicacids. Hence, based on this visual information, the user can readilycharge the system 1 with the required consumables. Charging of thesystem 1 with consumables can be performed by manual and/or automaticcharging operations.

In order to determine the presence of objects, the ultrasonic sensors 28are moved over the intended locations of the tip trays 17 by means ofthe transfer head 29. Stated more particularly, when moving theultrasonic sensors over the tip trays 17, first acoustic waves aregenerated and emitted towards the intended locations of the processingplates 15, with first signals (time between emission of acoustic wavesand reception of reflected acoustic waves) of the reflected firstacoustic waves being measured. Furthermore, at least one second acousticwave is generated and emitted towards a predetermined surface (such as adedicated reference surface) of the tip tray rack 5, with a secondsignal (time between emission of acoustic waves and reception ofreflected acoustic waves) of the reflected second acoustic wave beingmeasured. The determination of the presence of the tips contained in thetip trays 17 is similarly performed, except for emitting the at leastone second acoustic wave towards a predetermined surface of each of thetip trays 17 and measuring second signals of the second acoustic wavesreflected therefrom.

Similarly, when moving the ultrasonic sensors 28 over the intendedlocations of the processing plates 15, first acoustic waves aregenerated and emitted towards the intended locations of the processingplates 15, with first signals (round-trip-times) of the reflected firstacoustic waves being measured. Furthermore, at least one second acousticwave is generated and emitted towards a predetermined surface of theprocessing rack 4, with a second signal (round-trip-time) of thereflected second acoustic wave being measured.

The determination of the presence of objects is analogously repeated foreach of the consumables to be used for processing of nucleic acidscontaining fluids, with the presence of objects being either determinedwith respect to the rack to which it belongs or with respect to theplate, tray or cartridge to which it belongs.

Alternatively, the determination of the presence of objects may be basedon determining distances of the reflecting surfaces from the ultrasonicsensor based on the resulting round-trip-time (time-of-travel)measurements.

Then a subroutine “CHECK FLUID LEVELS” (process step IV) starts. Thissubroutine starts a control run in which the ultrasonic sensors 28 aremoved over one or both of the processing plates 15 containing thenucleic acids containing fluids, in which the fluid levels aredetermined as detailed-below in connection with FIG. 6.

The racks 3-8 are kept stationary during determining the presence ofconsumables and fluid levels of the fluids contained in the processingplates 15.

In the following process step (process step V), for each of theconsumables to be used, the first and second signals are compared witheach other in calculating a difference of the first and second signals(round-trip times or distances). The difference of the signals then iscompared with an intended difference of signals as defined by theprocess operation plan. In case the difference of signals matches theintended difference of signal amplitudes, it is assumed that theconsumable concerned is in its target position. Furthermore, determinedfluid levels of fluids contained in the processing plates 15 arecompared with intended fluid levels as defined by the process operationplan. In case the fluid levels match the intended fluid levels, it isassumed that the fluid levels are correct.

In case a mismatch concerning the presence of consumables is determined,a message is displayed on the display 35 containing information guidingthe user to load missing and/or misplaced disposables (process step VI).In case a mismatch concerning the fluid levels is determined, anothermessage is displayed on the display 35 containing information guidingthe user to load the missing fluids (process step VI).

Otherwise, the display 35 can, e.g., display the work-plate 2 or one ormore parts thereof in a manner to visualize a possible mismatch betweenthe consumables actually present in the system 1 and the requiredconsumables as defined by the process operation plan. Based on thisvisual information, the user can verify the result of the chargingoperation and can readily add missing consumables, e.g., by a manualcharging operation.

Having loaded the missing or misplaced consumables and/or nucleic acidscontaining fluids, the user can re-start the subroutine “CHECK PRESENCE”and/or the subroutine “CHECK FLUID LEVELS” as desired actuating thecontrol computer 34.

In case there is no mismatch determined, another subroutine “EXTRACTION”(process step VIII) is started for performing the steps for extractingthe nucleic acids which is not further detailed herein, which ends whenpurified nucleic acids have be obtained (process step IX).

When performing the subroutine “EXTRACTION”, subroutine “CHECK PRESENCE”as illustrated in FIG. 5A, and subroutine “CHECK FLUID LEVELS” asillustrated in FIG. 5B may be performed.

The symbols of the flowchart of FIG. 5A have the following meaning:

I′: START SUBROUTINE “CHECK PRESENCE”

II′: MISMATCH?

III′: DISPLAY MESSAGE

IV′: INITIATE RE-START SUBROUTINE “CHECK PRESENCE”

In case during extraction of nucleic acids arises a need of manuallyand/or automatically refilling of consumables, e.g., due to alow-storage capacity of the system 1, presence of refilled consumablesin their intended locations has to be automatically checked prior tocontinuing nucleic acids extraction. Accordingly the subroutine “CHECKPRESENCE” as already above-detailed is started (process step I′) tocheck if there is a mismatch between a difference of signal values andan intended difference of signal values (process step II′) as defined bythe process operation plan. In case of mismatch, a message is displayedon the display 35 (process step III′), so that the user can restart thesubroutine “CHECK PRESENCE” (process step IV′) actuating the controlcomputer 34 as desired. In case of no mismatch, the subroutine“EXTRACTION” is continued.

The symbols of the flowchart of FIG. 5B have the following meaning:

-   -   I″: START SUBROUTINE “CHECK FLUID LEVELS”    -   II″: MISMATCH?    -   III″: DISPLAY MESSAGE/INITIATE FLUID LEVEL CORRECTION/INITIATE        RESTART SUBROUTINE “CHECK FLUID LEVELS”

In case of pipetting fluids during extraction of the nucleic acids, aneed may arise to check the fluid level of fluids after pipetting.Accordingly the subroutine “CHECK FLUID LEVELS” as detailed below isstarted (process step I″) to check if there is a mismatch between theactual fluid levels and the intended fluid levels (process step II″) asdefined by the process operation plan. In case of mismatch, a message isdisplayed on the display and/or the user can initiate an automated fluidlevel correction and/or the user can restart the subroutine “CHECK FLUIDLEVELS” actuating the control computer 34. In case of no mismatch, thesubroutine “EXTRACTION” is continued.

Accordingly, prior to starting and/or during nucleic acids containingfluid processing, the presence of consumables to be used for theprocessing of fluids in intended positions as defined by the processoperation plan is controlled scanning the consumables by means of theultrasonic sensors 28.

Additionally, an identity and/or orientation of individual consumableswith respect to their intended positions as defined by the processoperation plan may be performed, e.g., determining a geometric profile,in particular a height profile (height pattern), of individual objectswhich is compared with an intended profile for the consumable concerned.

Due to the linear sensor array 27, adapted to the rows of the planararrays of plates and trays, presence of consumables contained thereinand/or fluid levels of fluids contained therein may be efficientlycontrolled in parallel when moving the sensor array 27 along thestacking direction of rows and simultaneously determining the presenceof objects and/or fluid levels.

Intended signal values as defined by the process operation plan may bereadily adapted in calibrating the ultrasonic sensor signals usingreference surfaces of the racks and plates, respectively.

Reference is now made to FIG. 6 illustrating a diagram depicting atime-of-travel indicating curve for determining fluid levels in theoutput plate 16 using the sensor array 27 of the system 1.

Specifically, FIG. 6 indicates time-of-travel measurements of anultrasonic sensor 28 which is continuously moved along the seconddirection (stacking direction of rows) as indicated by arrow 32 (seeFIG. 1) of the output plate 16. The x-axis of this diagram is indicatinga travel time of the positioning device which relates to a position onthe process area given a reference/starting position of the positioningdevice and its velocity. The time-of-travel measurements are obtained intransmitting acoustic waves towards the output plate 16 and receivingthe acoustic waves upon reflection to thereby determine a time intervalbetween transmitted and received acoustic waves. The y-axis of thisdiagram depicts the turn-around time of an acoustic wave emitted by theultrasonic sensor, reflected (vertically) from the location of theprocess area underneath and received by the ultrasonic sensor.Accordingly, a time-of-travel profile of the output plate 16 as seen bythe ultrasonic sensor 28 is obtained.

When interpreting the time-of-travel profile of FIG. 6, positions ofindividual wells along the second direction can be determined based on adetection of falling and rising edges with respect to a reference level(R0 to R12) which corresponds to the plane level of the output plate 16.Having identified each of the wells, well levels W1 to W12 in-betweenadjacent falling and rising edges corresponding to fluid levels in thewells are determined, for instance, e.g., using the mean function or thehighest value between the edges. Accordingly, as a result of aboveanalysis, the output plate 16 is determined to include seven half-fullwells and five empty wells.

Using the ultrasonic sensors 28 of the linear sensor array 27 in a wayas exemplified in FIG. 6 for a single ultrasonic sensor 28, all wells ofthe output plate 16 can be efficiently scanned with respect to fluidlevel detection in a single run.

Alternatively, the sensor array 27 may be continuously moved along thefirst direction (direction according to which wells are arranged inindividual rows) as indicated by arrow 33 (see FIG. 1) of the outputplate 16. Yet alternatively, the sensor array 27 may continuously movedto perform a combined movement along the first and second directions ofthe output plate 16.

Combining movements of the pipetting tips 22 for pipetting of liquidsfor the automated extraction of nucleic acids with movements of theultrasonic sensors 28 for detecting of fluid levels, the outcome ofpipetting operations may be efficiently controlled by fluid leveldetection, for instance, in performing pipetting operations when movingthe transfer head 29 in one direction of travel and performing fluidlevels detection when moving the transfer head 29 in an oppositedirection of travel. More particularly, when determining fluid levelsprior to pipetting operations and also after the pipetting operations,pipetted volumes may be determined. Basically, information obtained inscanning along one dimension can be considered sufficient in caseconsumables are symmetrically arranged along such scanning directions.

FIG. 7 depicts an exemplary screen display of the display 35 of targetpositions of objects. A process operation plan according to thisembodiment comprises a section for supporting the loading of objectsonto the work-plate 2 of the system 1. As described in respect of FIGS.4 and 5 the user of the control computer 34 selects a process operationplan from a menu. The process operation plan then continues and displaysthe objects to be loaded on a screen display as shown in FIG. 7. It canbe seen that the screen display is a schematic representation of thework-plate 2 as shown in FIG. 2. Reference numerals in FIG. 7 have adash to indicate that the numbers are used for screen representations oflike objects in FIG. 2.

As can be seen in FIG. 7 the user is instructed by the screen display toload bottles 20′ which are MGP bottles (i.e. bottles holding asuspension of magnetic glass particles) and DNAse reagent bottles (i.e.a DNA digesting reagent) into the indicated positions (target positions)in the bottle rack 8′. Further the first reagent rack 6′ needs to befilled with the reagent plate 18′ (processing cartridge) and twospecific reagents 37′. The tip tray rack 5′ needs to be filled with twotip trays 17′ pre-filled with tips and the processing rack 4′ is to befilled with the processing plate 15′ (sample cartridge) and the outputplate 16′. When the user has disposed the objects accordingly he canpress an OK button and the control computer 34 proceeds with the processoperation plan. As described above it is checked with one or moreultrasonic sensors 28 if objects are present in the prescribedpositions. As also described before, it may be further checked by theprofile of the objects if proper objects have been loaded. By this itcan be for example detected when tips have been loaded in a position forreagents.

Loading mistakes can be signalled to the user by e.g. text messages as“please load tips” or “sample cartridge is missing”.

Further a similar screen display as depicted in FIG. 7 can be employedto signal loading mistakes by colour coded representation of missingobjects or misplaced objects. E.g. a missing tip tray can be depicted inred and flashing.

Accordingly, by the above discussion, a system 1 for the automatedprocessing of fluids according to a process operation plan involving theuse of preloaded objects, in which the process operation plan definespreloaded objects to be present in target object positions, has beendisclosed. The system comprises: a processing area 2 in which objects13-20 to be used for the processing of fluids are located; at least oneultrasonic sensor 28, adapted for determining the presence of objects13-20 by means of acoustical waves; a positioning device 23 to which theultrasonic sensor 28 is fixed, adapted to move the ultrasonic sensor 28in at least one direction relative to said processing area 2; a controlcomputer 34 being configured to determine the presence of objects 13-20and determining if objects 13-20 are present in target object positions(e.g., retaining sections 12) in said processing area 2 as defined bysaid process operation plan; at least one pipetting device 21, 26 forpipetting of fluids between cavities located in said processing area 2;and an analytical or pre-analytical processing device 36 for processingof fluids located in said processing area 2.

In another embodiment, the system 1 further comprises a plurality ofultrasonic sensors 28 arranged in a sensor array 27, said controlcomputer 34 being configured to simultaneously determine the presence ofobjects 13-20 and determining if objects are present in said targetobject positions 12 as defined by said process operation plan.

In another embodiment, the system 1 further comprises a signalizingdevice 35, wherein said control computer 34 being configured tosignalize a mismatch between objects present and objects required insaid target object positions 12 as defined by said process operationplan.

In another embodiment, the signalizing device is a display 35, and thecontrol computer 34 is configured to display a representation of one ormore parts of said system 1 in order to visualize said target objectpositions 12 as defined by said process operation plan.

In another embodiment, the system 1 further comprises at least oneholder 3-8, adapted to hold said preloaded objects 13-20 in said targetobject positions 12.

In another embodiment, a method has been disclosed for determining thematching of objects present in a processing area 2 in an instrument 1(system) with preloaded objects to be present in target object positions12 in said instrument according to a process operation plan. The methodcomprises the following steps: determining the presence of objects 13-20relative to the processing area 2 in said instrument by means of atleast one ultrasonic sensor 28; and determining if objects 13-20 arepresent in target object positions 12 as defined by said processoperation plan.

In another embodiment, the method further includes a step of outputtinga message to a signalizing device 35 based on a result of saiddetermination if objects are present in said target object positions 12as defined by said process operation plan.

In another embodiment, the method further includes a step of displayinga representation of one or more parts of the system 1 in order tovisualize the target object positions 12 as defined by said processoperation plan.

In another embodiment, the method further includes a step of displayinga mismatch between objects present and objects required in said targetobject positions 12 as defined by said process operation plan.

In another embodiment, the message contains user-guiding informationabout objects 13-20 to be loaded in target object positions 12 into saidinstrument 1.

In another embodiment, the method further including a step ofdetermining identity and/or orientation relative to said instrument 1 ofobjects 13-20 present in said instrument.

In another embodiment, determining the presence of objects 13-20relative to said instrument by said at least one ultrasonic sensor 28involves moving of the ultrasonic sensor, wherein moving of theultrasonic sensor is combined with moving of a pipetting device 21 forpipetting of fluids.

In another embodiment, the method further includes a step of determiningof fluid levels of fluids contained in cavities by means of said atleast one ultrasonic sensor 28.

In another embodiment, determining of fluid levels involves measuring ofdistance values of said cavities with respect to a reference distancelevel as defined by a plane said cavities are arrayed in.

In still another embodiment, a method for the automated processing offluids according to a process operation plan involving the use ofpreloaded objects, comprises utilizing any of the above describedmethods according to the present invention.

Obviously many modifications and variations of the present invention arepossible in light of the above description. It is therefore to beunderstood, that within the scope of appended claims, the invention maybe practiced otherwise than as specifically devised.

1. A system for the automated processing of fluids according to aprocess operation plan involving the use of preloaded objects, saidprocess operation plan defining preloaded objects to be present intarget object positions, said system comprising: a processing area inwhich objects to be used for the processing of fluids are located; atleast one ultrasonic sensor for determining the presence of objects byacoustical waves; a positioning device to which the ultrasonic sensor isfixed and which moves the ultrasonic sensor in at least one directionrelative to said processing area; a control computer determining thepresence of objects and determining if objects are present in targetobject positions in said processing area as defined by said processoperation plan; at least one pipetting device for pipetting of fluidsbetween cavities located in said processing area; and an analytical orpre-analytical processing device for processing of fluids located insaid processing area.
 2. The system according to claim 1, comprising aplurality of ultrasonic sensors arranged in a sensor array, said controlcomputer simultaneously determines the presence of objects anddetermines if objects are present in said target object positions asdefined by said process operation plan.
 3. The system according to claim1, further comprising a signalizing device, wherein said controlcomputer signals a mismatch between objects present and objects requiredin said target object positions as defined by said process operationplan with said signalizing device.
 4. The system according to claim 3,wherein said signalizing device is a display, and wherein said controlcomputer displays a representation of one or more parts of said systemin order to visualize said target object positions as defined by saidprocess operation plan.
 5. The system according to claim 1, furthercomprising at least one holder to hold said preloaded objects in saidtarget object positions.
 6. The system according to claim 1, furthercomprising a holder, and wherein the control computer providesuser-guiding information about the objects to be loaded in said targetobject positions into the holder.
 7. The system according to claim 1,wherein the control computer determines identity and/or orientation ofthe objects present in said system.
 8. The system according to claim 1,wherein the control computer determines the presence of objects bymoving the ultrasonic sensor combined with moving the pipetting device.9. The system according to claim 1, wherein the control computerdetermines fluid levels of fluids contained in the cavities by use ofthe ultrasonic sensor.
 10. The system according to claim 9, wherein thecontrol computer determines the fluid levels by measuring with theultrasonic sensor distance values of said cavities with respect to areference distance level as defined by a plane said cavities are arrayedin.
 11. A method for determining the matching of objects present in aprocessing area in an instrument with preloaded objects to be present intarget object positions in said instrument according to a processoperation plan, comprising: determining the presence of objects relativeto the processing area in said instrument by means of at least oneultrasonic sensor; and determining if objects are present in targetobject positions as defined by said process operation plan.
 12. Themethod according to claim 11, further comprising outputting a message toa signalizing device based on a result of said determination if objectsare present in said target object positions as defined by said processoperation plan.
 13. The method according to claim 12, further comprisingdisplaying a representation of one or more parts of the system in orderto visualize the target object positions as defined by said processoperation plan.
 14. The method according to claim 12, further comprisingdisplaying a mismatch between objects present and objects required insaid target object positions as defined by said process operation plan.15. The method according to claim 12, wherein said message containsuser-guiding information about objects to be loaded in target objectpositions into said instrument.
 16. The method according to claim 11,further comprising determining identity and/or orientation relative tosaid instrument of objects present in said instrument.
 17. The methodaccording to claim 11, wherein determining the presence of objectsrelative to said instrument by means of said at least one ultrasonicsensor involves moving of the ultrasonic sensor, wherein moving of theultrasonic sensor is combined with moving of a pipetting device forpipetting of fluids.
 18. The method according to claim 11, furthercomprising determining of fluid levels of fluids contained in cavitiesby means of said at least one ultrasonic sensor.
 19. The methodaccording to claim 18, wherein determining of fluid levels involvesmeasuring of distance values of said cavities with respect to areference distance level as defined by a plane said cavities are arrayedin.
 20. A method for the automated processing of fluids according to aprocess operation plan involving the use of preloaded objects,comprising utilizing a method according to claim 11.